To date, there are no effective therapies that can counteract the damaging effects of cigarette smoke exposure in the lung. In fact, the age-adjusted mortality for chronic obstructive pulmonary disease (COPD) has risen 71% over the past thirty years. To improve this trend more effective strategies of treating the underlying disease mechanisms need to be developed. Aberrant activation of signaling kinases exerts a central role on the pathophysiologic responses that occur in this disease. The activity of these kinases is tightly regulated by intracellular phosphatases;however, our knowledge of the role of these proteins in the pathogenesis of COPD is extremely limited. PP2A is the major serine threonine protein phosphatase present in all eukaryotic cells. Among its many functions, it dephosphorylates and inactivates both JNK and c-Jun;thus, it is a major regulator of the TNF signaling pathway in the lung. We have recently published that superoxide dismutase-1 (SOD1), a lung antioxidant, prevents cigarette smoke-induced inflammation and emphysema formation in mice. Further studies in our laboratory demonstrated that SOD1 and glutathione peroxidase-1 (GPX1) increase PP2A activity and decrease AP-1 activation in the lungs of these transgenic mice. This indicates that antioxidants, via their effects on PP2A, can alter the activation state of this pivotal signaling pathway in this disease. We hypothesize that antioxidants protect against smoke-induced lung injury by enhancing PP2A activity thereby decreasing AP-1 signaling in the lung. This hypothesis is based on three important findings from prior studies in our laboratory: 1) SOD1/GPX1 increases PP2A activity in the lung without altering expression or protein levels, 2) Increases in PP2A activity in the lungs of mice is associated with reduced AP-1 nuclear binding in the lung and 3) JNK inhibition decreases cigarette smoke-induced lung inflammation in mice. This proposal will address how antioxidants alter PP2A activity (Aim 1). In addition, it will determine whether increasing PP2A activity counters TNF signaling and smoke-induced lung injury in this disease (Aim 2). Finally, it will address if PP2A activity or distribution alters TNF signaling in the lungs of emphysema patients (Aim 3). We believe that the insights gained from these studies will provide more targeted strategies of treating this disease and have the strong potential to make a significant contribution to public health in the future. Moreover, our findings will have important implications not only for COPD but also for other diseases where TNF signaling and inflammation play a central role. PUBLIC HEALTH RELEVANCE: While a significant body of research has elucidated the role that protein kinases exert in COPD, much less is know about the effects of protein phosphatases. This proposal will advance public health by determining how PP2A, the primary eukaryotic serine/threonine phosphatase, alters the injurious responses to cigarette smoke exposure in the lung.